The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
A variety of disorders in humans and other mammals involve or are associated with abnormal bone resorption. Such disorders include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget""s disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. One of the most common of these disorders is osteoporosis, which in its most frequent manifestation occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, are generally chronic conditions, it is believed that appropriate therapy will typically require chronic treatment.
Normal bone physiology involves a process wherein bone tissue is continuously being turned over by the processes of modeling and remodeling. In other words, there is normally an appropriate balance between resorption of existing bone tissue and the formation of new bone tissue. The exact mechanism underlying the coupling between bone resorption and formation is still unknown. However, an imbalance in these processes is manifested in various disease states and conditions of the skeleton.
Two different types of cells called osteoblasts and osteoclasts are involved in the bone formation and resorption processes, respectively. See H. Fleisch, Bisphosphoizates In Boise Disease, From The Laboratory To The Patient, 3rd Edition, Parthenon Publishing (1997), which is incorporated by reference herein in its entirety.
Osteoblasts are cells that are located on the bone surface. These cells secrete an osseous organic matrix, which then calcifies. Substances such as fluoride, parathyroid hormone, and certain cytokines such as protaglandins are known to provide a stimulatory effect on osetoblast cells. However, an aim of current research is to develop therapeutic agents that will selectively increase or stimulate the bone formation activity of the osteoblasts.
Osteoclasts are usually large multinucleated cells that are situated either on the surface of the cortical or trabecular bone or within the cortical bone. The osteoclasts resorb bone in a closed, sealed-off microenvironment located between the cell and the bone. The recruitment and activity of osteoclasts is known to be influenced by a series of cytokines and hormones. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone resorption, making these compounds important therapeutic agents in the treatment or prevention of a variety of systemic or localized bone disorders caused by or associated with abnormal bone resorption. However, despite the utility of bisphosphonates there remains the desire amongst researchers to develop additional therapeutic agents for inhibiting the bone resorption activity of osteoclasts.
Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. A natural prostaglandin, PGE2, has the following structure. 
Prostaglandins such as PGE2 are known to stimulate bone formation and increase bone mass in mammals, including man. It is believed that four different receptor subtypes, designated EP 1, EP2, EP3, and EP4 are involved in mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts. The major prostaglandin receptor in bone is EP4, which is believed to provide its effect by signaling via cyclic AMP. However, the scientific information that is currently known about the prostaglandin mediated bone effect is rather limited, because the exact mechanism of action is not known. Prostaglandins and their accosted receptors are more fully described in for example, K. Ono et al., Inportant role of EP4, a subtype ofprostaglandin (PG) E receptor, in osteoclast-like cell formation from2 mouse bone marrow cells induced by PGE2, J. of Endocrinology, 158, R1-R5 (1998), C. D. Funk et al., Cloning and Expression of a cDNA for the Human Prostaglandin E Receptor EP! Subtype, Journal of Biological Chemistry, vol. 268, no. 35, pp. 26767-26772 (1993), J. W. Reagan et al., Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP2 Subtype, Molecular Pharmacology, vol. 46, pp. 213-220 (1994), J. Yang et al., Cloning and Expression of the EP3-Subtype of Human Receptors for Prostaglandin E2, Biochemical Biophysical Research Communication, vol., 198, pp. 999-1006 (1994), L. Bastien et al., Cloning, Functional Expression and Characterization of the Human Prostaglandin E2 Receptor EP2 Subtype, Journal Biological Chemistry, vol. 269, pp. 11873-11877 (1994), which are all incorporated by reference herein in their entirety.
In the present invention it is found that antagonists of the EP4 subtype receptor are useful for inhibiting bone resorption. Without being limited by theory, it is believed that these antagonists are responsible for inhibiting the bone resorption activity of the osteoclasts.
It is an object of the present invention to provide methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
It is another object of the present invention to provide methods for treating or reducing the risk of contracting a disease state or condition in a mammal in need of such treatment or prevention, comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist.
It is another object of the present invention to provide methods for inhibiting bone resorption in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
It is another object of the present invention to provide pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist.
It is another object of the present invention to provide pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
It is another object of the present invention to identify EP4 receptor subtype antagonists useful for inhibiting bone resorption.
These and other objects will become readily apparent from the detailed description which follows.
The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist having an EC50 value of from about 0.1 nanoM to about 100 microM.
In further embodiments, the present invention relates to methods for treating or reducing the risk of contracting a disease state or condition involving bone tissue in a mammal in need of such treatment or risk reduction, comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist.
In further embodiments, the present invention relates to methods for inhibiting bone resorption in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
In further embodiments, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist.
In further embodiments, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
In further embodiments, the present invention relates to a method for identifying antagonists of an EP4 receptor subtype.
In further embodiments, the present invention relates to the use of a composition in the manufacture of a medicament for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
All percentages and ratios used herein, unless otherwise indicated, are by wveight. The invention hereof can comprise, consist of, or consist essentially of the essential as well as optional ingredients, components, and methods described herein.
The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist having an EC50 value of from about 0.1 nanoM to about 100 microM.
Prostaglandins E (especially PGE2) stimulate bone formation and increase bone mass in several species, including man. The mechanism of this effect, the target cells and the receptors involved are not completely known. Specific cell-surface receptors for PGE2, such as EP1-4, which employ different secondary messenger systems have been cloned and characterized. It is believed that cyclic AMP may have a role in osteogenesis induced by PGE2. The expression of the EP2 and EP4 receptors is found to be involved in cAMP production in the bone tissue of young adult rats (where PGE2 is markedly anabolic), and in various osteoblastic cell lines. Osteoblastic cell lines, RCT-1, RCT-3, TRAB-11 and RP-1, as well as osteoblastic cells harvested from fetal rat bones express EP4 mRNA but not EP2 mRNA. In addition, EP4 mRNA is expressed in tibiae and calvariae of 5-week-old rats while EP2 is not. Treatment of periosteal cells (RP-1) in vitro with 10xe2x88x926M PGE2 increases the level of EP4 mRNA which peaks at 2 hours. Similarly, systemic administration of an anabolic dose of PGE2 (3-6 mglkg) to young adult rats upregulates the expression of EP4 in tibiae and calvariae, an effect which peaks at 1-2 hours. Using in-situ hybridization it is found that the increased expression of EP4 mRNA in the tibial metaphysis following systemic PGE2 treatment is localized to bone marrow cells.
EP4 is expressed in osteoblastic cells in vitro and in bone marrow utative osteoprogenitor cells in vivo and is upregulated by its ligand, PGE2. Given he presence of EP4 expression in the cells examined and in bone tissue, it is believed hat EP4 is the receptor subtype which mediates the anabolic effects of PGE).
Prostaglandins (especially PGE2) have multiple effects on bone, timulating both resorption and formation. Systemic administration of PGE2 or E1 to infants and to animals is clearly anabolic, stimulating bone formation and increases bone mass. Also local administration of PGE2 into long bones stimulates new bone formation, suggesting that that PGE2 acts directly on bone tissue to induce osteogenesis. Histological analysis of bones treated with PGE2 indicates that PGE2 increases the number of osteoblasts present on the bone surface, suggesting that prostaglandins act by recruiting osteoblasts from their precursors.
PGEs act on various cells via specific cell-surface receptors divided into 4 subtypes, EP1-4, according to their relative sensitivity to selective agonists and antagonists. The receptor subtypes all belong to the G-protein-coupled receptor family and activate different secondary messenger systems such as adenylate cyclase or phospholipase C. Of these 4 receptors, EP4 and EP2 activate adenylate cyclase, EP1 activates phospholipase C, and EP3 either lowers intracellular cAMP levels or activates phospholipase C, depending on the specific spliced variant.
In osteoblastic cells in vitro, PGE2 stimulates both phosphatidylinositol and cyclic AMP transduction pathways. Both EP 1 and EP4, found in osteoblastic MC3T3-E1 cells are believed to play a role in the biological action of PGE2 in bone tissue. Also PGE1, a potent inducer of bone formation in humans and other species, increases intracellular cyclic AMP but has no effect on phosphatidylinositol turnover in osteoblastic cells. It is therefor believed that PGE receptors coupled to adenylate cyclases, EP2 and/or EP4, are involved in osteogenesis. It is also believed that the cyclic AMP pathway is involved in the recruitment of osteoblasts from bone marrow cells. Initial characterization of in vivo expression of EP receptors by in situ hybridization shows that in embryonic and neonatal mice EP4 is the major form found in bone tissue, especially in preosteoblasts. See Ikeda T, Miyaura C, Ichikawa A, Narumiya S, Yoshiki S and Suda T, 1995, In situ localization of three subtypes (EP1, EP3 and EP4) of prostaglandin E receptors in embryonic and newborn mice. J Bone Miner Res 10 (sup 1):S172, which is incorporated by reference herein in its entirety.
Also, it is found that EP4 but not EP2 mRNA is expressed in adult rat one tissue and bone-derived cell lines and that expression is stimulated by PGE2.
Analysis of the in vivo expression of PGE receptors shows that EP4 but ot EP2 is expressed in total RNA from adult rat tibiae and calvariae. EP4 is believed to be the major adenylate cyclase-coupled PGE2 receptor expressed in osteoblastic cells and in bone tissue. Also, the EP4 receptor subtype is expressed in the bone tissue of young adult rats, in which PGE2 is strongly anabolic.
EP4 mRNA is expressed in osteoblast precursor cells. It is also found in less differentiated bone cell lines such as RCT-1, TRAB-11 and the RP-1 periosteal cells, but not in fibroblasts. It is highly expressed in bone marrow cells that include osteoblast precursor cells, but not in fully mature osteoblasts on the bone surface. It is believed that PGE2 induces osteogenesis via an increase in the number of active osteoblasts present on the bone surface, resulting from the recruitment of osteoblast precursor cells rather than the enhancement of the activity of existing osteoblasts.
It is found that osteoblast precursors are the major target cells for the anabolic effect of PGE2 and that its action in these cells is mediated by EP4. The EP4 receptor subtype is believed to be the major receptor which mediates the effects of PGE2 in bone tissue rats. Induction of EP4 by PGE2 further supports its biological role in the bone tissue and points to a mechanism of autoamplification of PGE action.
The present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
The methods and compositions of the present invention are useful for both treating and reducing the risk of disease states or conditions associated with abnormal bone resorption. Such disease states or conditions include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget""s disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
In further embodiments, the methods comprise administering a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active. Both concurrent and sequential administration of the EP4 receptor subtype antagonist and the bisphosphonate active are deemed within the scope of the present invention. With sequential administration, the antagonist and the bisphosphonate can be administered in either order. In a subclass of sequential administration the antagonist and bisphosphonate are typically administered within the same 24 hour period. In yet a further subclass, the antagonist and bisphosphonate typically administered within about 4 hours of each other.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d, as used herein, means that amount of the EP4 receptor subtype antagonist, or other actives of the present invention, that will elicit the desired therapeutic effect or response or provide the desired benefit when administered in accordance with the desired treatment regimen. A prefered therapeutically effective amount is a bone resorption inhibiting amount.
xe2x80x9cPharmaceutically acceptablexe2x80x9d as used herein, means generally suitable for administration to a manrrmal, including humans, from a toxicity or safety standpoint.
In the present invention, the agonist is typically administered for a sufficient period of time until the desired therapeutic effect is achieved. The term xe2x80x9cuntil the desired therapeutic effect is achievedxe2x80x9d, as used herein, means that the therapeutic agent or agents are continuously administered, according to the dosing schedule chosen, up to the time that the clinical or medical effect sought for the disease or condition being mediated is observed by the clinician or researcher. For methods of treatment of the present invention, the compounds are continuously administered until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass or a replacement of abnormal bone structure with normal bone structure are the desired objectives. For methods of reducing the risk of a disease state or condition, the compounds are continuously administered for as long as necessary to prevent the undesired condition. In such instances, maintenance of bone mass density is often the objective.
Nonlimiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal. For humans, administration periods can range from about 2 weeks to the remaining lifespan of the human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.
The present invention also relates to methods for identifying compounds useful as antagonists of the EP4 receptor subtype. Compounds so identified are useful for inhibiting bone resorption.
The present invention relates to a method for identifying compounds which antagonize an EP4 receptor subtype comprising:
a). contacting a putative antagonist of an EP4 receptor subtype with a cell culture; and
b). determining the antagonist activity of said putative agonist with a cell culture not contacted with said putative antagonist.
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of an EP4 receptor antagonist.
These compositions can further comprise a pharmaceutically-acceptable carrier. In further embodiments these compositions also comprise a bisphosphonate active.
The methods and compositions of the present invention comprise an EP4 receptor subtype antagonist.
The term xe2x80x9cantagonistxe2x80x9d as used herein, is used in its standard meaning to mean a chemical substance that opposed the physiological effects of another substance. In other words, an antagonist is a chemical substance that opposes the receptor-associated responses normally induced by another bioactive agent.
The antagonists useful herein generally have an EC50 value from about 0.1 nM to about 100 microM, although antagonists with activities outside this range can be useful depending upon the dosage and route of administration. In a subclass of the present invention, the antagonists have an EC50 value of from about 0.01 microM to about 10 microM. In a further subclass of the present invention, the antagonists have an EC50 value of from about 0.1 microM to about 10 microM. EC50 is a common measure of antagonist activity well known to those of ordinary skill in the art and is defined as the concentration or dose of an antagonist that is needed to produce half, i.e. 50%, of the maximal effect. See also, Goodman and Gilman""s, The Pharmacologic Basis of Therapeutics, 9th edition, 1996, chapter 2, E. M. Ross, Pharmacodynamics, Mechanisms of Drug Action and the Relationship Between Drag Conicentratioti Cand Effect, which is incoroporated by reference herein in its entirety.
Nonlimiting examples of antagonists useful herein are selected fom the group consisting of
5-butyl-2,4-dihydro-4-[[2xe2x80x2-[N-(3-chloro-2-thiophenecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-2-{2-(trifluoromethyl)phenyl]-1,2,4-triazol-3-one potassium salt,
5-butyl-2,4-dihydro-4-[[2xe2x80x2-[N-(2-methyl-3-furoyl)sulfamoyl]biphenyl4-yl]methyl]-2-[2-(trifluoromethyl)phenyl]-1,2,4-triazol-3-one,
5-butyl-2,4-dihydro-4-[[2xe2x80x2-[N-(3-methyl-2-thiophenecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-2-[(2-trifluoromethyl)phenyl]-1,2,4-triaol-3-one,
5-butyl-2,4-dihydro-4-[[2xe2x80x2-[N-(2-thiophenecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-2-[(2-trifluoromethyl)phenyl]-1,2,4-triaol-3-one,
5-butyl-2,4-dihydro-4-[[2xe2x80x2-[N-[2-(methylpyrrole)carbonyl]sulfamoyl]biphenyl-4-yl]methyl]-2-[(2-trifluoromethyl)phenyl-1,2,4-triazol-3-one,
and the pharmaceutically acceptable salts thereof, and mixtures thereof.
In the present invention, the antagonists useful herein are compounds that do not contain a cyclopentanone or hydroxycyclopentane ring. In other words, these are non-cyclopentanone and non-hydroxycyclopentane structures.
The methods and compositions of the present invention, can further comprise a bisphosphonate active. The bisphosphonates of the present invention correspond to the chemical formula 
wherein n is an integer from 0 to 7 and wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, C1-C30 substituted alkyl, C1-C10 alkyl substituted NH2, C3-C10 branched or cycloalkyl substituted NH2, C1-C10 dialkyl substituted NH2, C3-C10 branched or cycloalkyl disubstituted NE2, C1-C10 alkoxy, C1-C10 alkyl substituted thio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, and benzyl, such that both A and X are not selected from H or OH when n is 0; or A and X are taken together with the carbon atom or atoms to which they are attached to form a C3-C 10 ring.
In the foregoing chemical formula, the alkyl groups can be straight, branched, or cyclic, provided that sufficient atoms are selected for the chemical formula. The C1-C30 substituted alkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, C1-C10 alkyl or dialkyl substituted NH2, OH, SH, and C1-C10 alkoxy.
The foregoing chemical formula is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and/or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.
A non-limiting class of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and halogen, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, halogen, and C1-C30 alkyl or phenyl substituted thio, and n is 0.
A non-limiting subclass of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and C1, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, C1, and chlorophenylthio, and n is 0.
A non-limiting example of the subclass of structures useful in the instant invention is when A is OH and X is a 3-aminopropyl moiety, and n is 0, so that the resulting compound is a 4-amino-1,-hydroxybutylidene-1,1-bisphosphonate, i.e. alendronate.
Pharmaceutically acceptable salts and derivatives of the bisphosphonates are also useful herein. Nonlimiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-C1-C30-alkyl-substituted ammonium. Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts. Nonlimiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.
It should be noted that the terms xe2x80x9cbisphosphonatexe2x80x9d and xe2x80x9cbisphosphonatesxe2x80x9d, as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials. The use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those or ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein. For example, the phrase xe2x80x9cabout 5 mg of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basisxe2x80x9d means that the amount of the bisphosphonate compound selected is calculated based on 5 mg of alendronic acid. For other bisphosphonates, the amount of bisphosphonate is calculated based on the corresponding bisphosphonic acid.
Nonlimiting examples of bisphosphonates useful herein include the following:
Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.
Alendronate (also known as alendronate sodium or alendronate monosodium trihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate.
Alendronic acid and alendronate are described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which are incorporated by reference herein in their entirety.
Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yamanouchi (cimadronate), as described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990, which is incorporated by reference herein in its entirety.
1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are incorporated by reference herein in their entirety.
1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid (EB-1053).
1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, also known as BM-210955, Boehringer-Mannheim (ibandronate), is described in U.S. Pat. No. 4,927,814, issued May 22, 1990, which is incorporated by reference herein in its entirety.
6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (nenrdronate).
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate).
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).
[2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate) is described in U.S. Pat. No. 4,761,406, which is incorporated by reference in its entirety.
1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid (risedronate).
(4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) as described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989, which is incorporated by reference herein in its entirety.
1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (zolendronate).
A non-limiting class of bisphosphonates useful in the instant invention are selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
A non-limiting subclass of the above-mentioned class in the instant case is selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
A non-limiting example of the subclass is alendronate monosodium trihydrate.
The EP4 receptor subtype antagonists, and in further embodiments the bisphosphonate actives and any other additional actives are typically administered in admixture with suitable pharmaceutically acceptable diluents, excipients, or carriers, collectively referred to herein as xe2x80x9ccarrier materialsxe2x80x9d, suitably selected with respect to the mode of administration. Nonlimiting examples of product forms include tablets, capsules, elixirs, syrups, powders, suppositories, nasal sprays, liquids for ocular administration, formulations for transdermal administration, and the like, consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet, capsule, or powder, the active ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like. For oral administration in liquid form, e.g., elixirs and syrups, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated. Suitable binders can include starch, gelatin, natural sugars such a glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. An example of a tablet formulation is that described in U.S. Pat. No. 5,358,941, to Bechard et al, issued Oct. 25, 1994, which is incorporated by reference herein in its entirety. The compounds used in the present method can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl-methacrylamide, and the like.